Division of Oncology, Department of Radiological, Oncological and Pathological Science, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy.
Laboratory of Tumor Immunology and Cell Therapies, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
J Transl Med. 2024 Apr 3;22(1):329. doi: 10.1186/s12967-024-05142-6.
Immune checkpoint inhibitors (ICIs), administered alone or combined with chemotherapy, are the standard of care in advanced non-oncogene addicted Non-Small Cell Lung Cancer (NSCLC). Despite these treatments' success, most long-term survival benefit is restricted to approximately 20% of patients, highlighting the need to identify novel biomarkers to optimize treatment strategies. In several solid tumors, immune soluble factors, the activatory CD137 Tcells, and the immunosuppressive cell subsets Tregs and MDSCs (PMN(Lox1)-MDSC and M-MDSCs) correlated with responses to ICIs and clinical outcomes thus becoming appealing predictive and prognostic factors. This study investigated the role of distinct CD137 Tcell subsets, Tregs, MDSCs, and immune-soluble factors in NSCLC patients as possible biomarkers.
The levels of T cells, MDSCs and soluble factors were evaluated in 89 metastatic NSCLC patients who underwent ICIs as first- or second-line treatment. T cell analysis was performed by cytoflurimetry evaluating Tregs and different CD137 Tcell subsets also combined with CD3, CD8, PD1, and Ki67 markers. Circulating cytokines and immune checkpoints were also evaluated by Luminex analysis. All these parameters were correlated with several clinical factors (age, sex, smoking status, PS and TPS), response to therapy, PFS , and OS . The analyses were conducted in the overall population and in patients treated with ICIs as first-line (naïve patients).
In both groups of patients, high levels of circulating CD137 and CD137PD1 T cells (total, CD4 and CD8) and the soluble factor LAG3 positively correlated with response to therapy. In naïve patients, PMN(Lox1)-MDSCs negatively correlated with clinical response, and a high percentage of Tregs was associated with favorable survival. Moreover, the balance between Treg/CD137 Tcells or PMN(Lox1)-MDSC/CD137 Tcells was higher in non-responding patients and was associated with poor survival. CD137 Tcells and Tregs resulted as two positive independent prognostic factors.
High levels of CD137, CD137PD1 Tcells and sLAG3 could predict the response to ICIs in NSCLC patients independently by previous therapy. Combining the evaluation of CD137 Tcells and Tregs also as Treg/CD137 T cells ratio it is possible to identify naive patients with longer survival.
免疫检查点抑制剂（ICIs）单独使用或与化疗联合使用是晚期非致癌基因依赖型非小细胞肺癌（NSCLC）的标准治疗方法。尽管这些治疗方法取得了成功，但大多数长期生存获益仅限于约 20%的患者，这凸显了需要确定新的生物标志物来优化治疗策略的必要性。在几种实体瘤中，免疫可溶性因子、活化的 CD137 T 细胞以及免疫抑制性细胞亚群 Tregs 和 MDSCs（PMN(Lox1)-MDSC 和 M-MDSC）与对 ICI 的反应和临床结果相关，因此成为有吸引力的预测和预后因素。本研究探讨了不同的 CD137 T 细胞亚群、Tregs、MDSCs 和免疫可溶性因子在 NSCLC 患者中的作用，作为可能的生物标志物。
对 89 名接受 ICI 作为一线或二线治疗的转移性 NSCLC 患者进行 T 细胞、MDSC 和可溶性因子水平评估。通过细胞荧光术评估 Tregs 和不同的 CD137 T 细胞亚群，并结合 CD3、CD8、PD1 和 Ki67 标志物进行分析。通过 Luminex 分析还评估了循环细胞因子和免疫检查点。将所有这些参数与几种临床因素（年龄、性别、吸烟状况、PS 和 TPS）、对治疗的反应、PFS 和 OS 相关联。在总体人群和接受 ICI 作为一线治疗（初治患者）的患者中进行了分析。
在两组患者中，循环 CD137 和 CD137PD1 T 细胞（总、CD4 和 CD8）和可溶性因子 LAG3 的高水平与治疗反应相关。在初治患者中，PMN(Lox1)-MDSC 与临床反应呈负相关，高 Tregs 百分比与生存良好相关。此外，非应答患者的 Treg/CD137 T 细胞或 PMN(Lox1)-MDSC/CD137 T 细胞平衡更高，与不良生存相关。CD137 T 细胞和 Tregs 是两个独立的阳性预后因素。
高水平的 CD137、CD137PD1 T 细胞和 sLAG3 可通过既往治疗独立预测 NSCLC 患者对 ICI 的反应。通过评估 CD137 T 细胞和 Tregs 以及 Treg/CD137 T 细胞的比值，可以识别出具有更长生存期的初治患者。
